Sensing light synthetically yields insight into retinal disease

A light shines into dark tubes on a rotating mixer

“Can we make yeast see?” seems an odd question for biologists to ask, but students in the Department of Cell & Systems Biology (CSB) have used synthetic biology to make yeast cells that can detect light.

Professor Belinda Chang studies the cells which respond to light in the retina and send that response as a signal to the brain. Her lab focuses on the light-sensitive rhodopsin protein molecule. She and her graduate students look at how these molecules work in species as diverse as mice, snakes, and bats, and why they stop working in humans who are losing their sight.

One day over a pizza lunch, the Chang lab graduate students discussed how they were each focused on a different species, which made it hard to compare results between projects. Making rhodopsin protein and studying its effect on other proteins in response to light were also very labour intensive experiments. The students decided to invent a system to test many types of rhodopsin in the same organism, rapidly and accurately.

Professor Chang supervised their project and the students produced their rhodopsin proteins in cells of brewers’ yeast. This synthetic biology approach took advantage of the fact that yeast cells can sense nearby yeast through a protein molecule known as a GPCR. GPCR molecules are found in organisms from yeast to mammals, and rhodopsin is also a GPCR. After replacing the yeast GPCR with human rhodopsin, shining light on the engineered yeast turned on a synthetic gene that made the yeast fluorescent.

This techniques was used to address a practical problem: patients who are losing their vision may have mutations in rhodopsin, but the severity of future vision loss can’t be judged based on mutation information alone.

Led by graduate student Ben Scott, this technique determined that variants of rhodopsin found in people afflicted with retinitis pigmentosa were less responsive to light in yeast, and that more clinically severe variants had even less of a response. Sergei Plotnikov’s lab provided support in characterizing the appearance of mutant rhodopsin, which enhanced the diagnostic value of the yeast system. This exciting result was published in the peer-reviewed journal Genetics as “Coupling of Human Rhodopsin to a Yeast Signaling Pathway Enables Characterization of Mutations Associated with Retinal Disease.

This work formed part of Ben Scott’s PhD in Chang’s lab at CSB. “Synthetic biology approaches can create new tools to help answer fundamental biological questions,” says Scott. “That’s really where this work fits in. But synthetic biology is a research field in its own right, working to create entirely new biological pathways and systems to solve problems in medicine and industry.“

This paper was recently awarded the Editors’ Choice Award for outstanding Molecular Genetics articles published in Genetics in 2019.